This invention relates to the enantiomers of 6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, prodrugs thereof and pharmaceutically acceptable salts and solvates of said enantiomers and prodrugs. The compounds of the present invention are useful in the treatment of hyperproliferative diseases, such as cancers, in mammals. The compounds are also useful as inhibitors of the enzyme farnesyl protein transferase, which is involved in cancerous tumor growth.
In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes (+) and (−) or d or I are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or I meaning that the compound is levorotatory and with (+) or d meaning that the compound is dextrotatory. For a given chemical structure the optically active isomers having opposite sign of optical rotation are called enantiomers. Said enantiomers are identical except that they are mirror images of each other. A 1:1 mixture of such enantiomer is called a racemic mixture.
It should be noted that optical rotation of chemical substances is dependent upon experimental parameters. The values shown hereinunder are specific rotations and the experimental conditions such as temperature, the wavelength of the plane polarized light used, the solvent as well as the concentration of the sample are indicated in the conventional way. The optical rotation may vary when for instance an acid addition salt is formed.
Stereochemical purity is of importance for biologically active substances that are used in pharmaceutical compositions for human application since the respective enantiomers may have a different potency or may have a different activity. Often, one of the enantiomers presents the desired optimum biological activity. Additionally, the presence of the other enantiomer in a composition or agent may cause or invigorate certain side effects. It is generally desirable to administer the biologically active substance in the form of a substantially pure enantiomer, which specifically exhibits the desired biological activity. Therefore, the resolution of a racemate into its enantiomers is often an important step in the preparation process of pharmacologically active substances.
The present invention provides for the enantiomers (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, and derivatives thereof. The invention further provides a number of processes to isolate the enantiomers (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one, and the derivatives thereof, in high yields and in a high enantiomeric excess (e.e.). More particularly, the invention relates to the process for production of enantiomerically pure and/or optically enriched (−)- and (+)-6-[(4-chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3-hydroxy-3-methyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one from a racemate mixture using continuous chromatography or chiral salt precipitation methods.